Bajaj, N

Bamiou, D-E

Davagnanam, I

Eriksson, SH

Houlden, H

Hwang, YT

Lakshmanan, R

Lynch, DS

Thompson, AGB

Warren, JD

UCL Discovery

Clinical/ScientificNotesYun Tae Hwang, MBBSRahul Lakshmanan,MBBSIndran Davagnanam,MBBChAndrew G.B. Thompson,MBBS, PhDDavid S. Lynch, MBBChHenry Houlden, MBBS,PhDNin Bajaj, BMBCh, PhDSofia H. Eriksson, MD,PhDDoris-Eva Bamiou,PYTHI, PhDJason D. Warren, MBBS,PhDNeurol Genet2017;3:e165; doi: 10.1212/NXG.0000000000000165Supplemental data atNeurology.org/ngBRAINSTEM PHENOTYPE OF CATHEPSIN A–RELATED ARTERIOPATHY WITH STROKES ANDLEUKOENCEPHALOPATHYCathepsin A–related arteriopathy with strokes andleukoencephalopathy (CARASAL) is a recentlyidentified cause of adult-onset cerebral leukodystro-phy due to CTSA gene mutations described in 3Dutch and British families.1,2 The clinical phenotypeof CARASAL continues to be defined. Here, wereport a British patient with CARASAL with brain-stem dysfunction as a leading clinical issue.Case description. A 48-year-old Caucasian woman(British CARASAL case2) presented with 5 years ofdeteriorating concentration and behavioral disinhi-bition. Recently, she had developed alternatingright- or left-sided facial pain of fluctuating inten-sity, which was ameliorated with carbamazepine.She also reported prominent, nonpositional vertigo,difficulty following conversations in noisy environ-ments, hyperacusis, tinnitus, and hoarseness. Hersleep was disturbed by vivid nightmares and fre-quent intrusive leg movements. Medical historyincluded migraine, hypertension, sinusitis, asthma,and depression. In the family history, her father diedat age 60 years after a stroke, and several paternalrelatives reportedly had young onset cognitivedecline, although no details were available. HerFolstein Mini-Mental State Examination score was27/30, losing points for orientation and generationof a novel sentence, and there was bedside evidenceof executive dysfunction and cognitive slowing,despite preserved memory and perceptual functions,corroborated on neuropsychometry. The generalneurologic examination was unremarkable.Brain MRI (figure, A–D) revealed diffuse, conflu-ent T2-weighted hyperintensity of supratentorial whitematter, basal ganglia, and thalamus with extensiveinvolvement of midbrain, pons, and medulla, includ-ing auditory pathways. Pure tone audiometry revealedsensorineural hearing loss with a “cookie-bite” profilemost marked for midfrequencies and transient otoa-coustic emissions, consistent with mild geneticcochlear dysfunction (figure, E; table e-1 at Neurol-ogy.org/ng). Auditory evoked brainstem responses at6 kHz showed delayed wave V (figure, F; table e-2):this was not attributable to cochlear dysfunction(given the normal wave I latency and 6–8 kHz tonedetection; figure, E, tables e-1 and e-2). Furthermore,a test of spatial noise perception3 showed abnormalbinaural interaction (table e-3), indicating (togetherwith the brainstem evoked responses) superior olivarynuclei involvement. Peripheral vestibular assessmentwith electronystagmography and caloric tests revealedsubtle smooth pursuit deficits, consistent with a brain-stem localization. Polysomnography revealed moderateperiodic limb movements of sleep and (althoughthere was no dream enactment) loss of REM atonia,suggestive of REM sleep behavior disorder.Extensive investigations for metabolic and geneticcauses of leukodystrophy proved unrevealing until thepatient was ultimately shown to have a pathogenicc.973C.T, p.R325C missense mutation in theCTSA gene, confirming the diagnosis of CARASAL.1The patient was found to share allele 123 at markerD20S838, indicating a common genetic ancestrywith previously reported Dutch cases.1Discussion. Initial descriptions of CARASAL haveemphasized stroke as a dominant clinical featureand relatively indolent cognitive decline, althoughmost patients have had memory complaints at presen-tation.1 In the series reported by Bugiani et al.,1symptoms of lower cranial nerve dysfunction (includ-ing vertigo, dysphagia, dry mouth, dry eyes, centralfacial paresis, or dysarthria) occurred in approximately70% of cases, and refractory hypertension was a fur-ther clinical hallmark. MRI changes commonlyinvolve brainstem white matter with additionalinvolvement of the thalami and other gray matternuclei,1 as in our case (figure, A–D). The audioves-tibular test profile here indicated a brainstem lesion,in addition to mild cochlear dysfunction of uncertainprovenance. Considered collectively, the available evi-dence suggests a potential brainstem substrate for thesymptom complex of facial pain, vertigo, hearing al-terations, hoarseness, and sleep disorder exhibited byour patient and similar symptoms described in pre-vious cases of CARASAL. The potential value ofbrainstem involvement in the differential diagnosisof CARASAL and related entities has not been pre-viously emphasized.Neurology.org/ng Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology 1At present, clinical differentiation of the cerebralarteriopathies exemplified by CARASAL, CARASIL,and CADASIL remains challenging.4 Although radio-logic involvement of brainstem white matter tracts isfrequently observed, neuro-otologic and other symp-toms referable to brainstem structures are relativelyuncommon in adult-onset leukodystrophies.5 InCADASIL, such symptoms are generally less salientthan cognitive and psychiatric decline.6 Based on theclinical evidence of the present case, we propose thatCARASAL should be considered in patients withadult-onset leukoencephalopathy and prominentearly symptoms implicating a brainstem origin. Thisproposal carries the caveat that clinical experiencewith CARASAL remains limited (at present, a singlegenetic variant1). Although the true prevalence andmechanism remain speculative, pending further stud-ies in larger cohorts with neuropathologic correlation,brainstem features in CARASAL could reflect dualeffects of dystrophic white matter tracts and impairedperfusion of cranial nerve nuclei due to perforantarteriopathy: a mechanism previously proposed tounderpin selective brainstem damage in CADASIL.7From the Dementia Research Centre (Y.T.H., J.D.W.), Departmentof Neurodegenerative Disease (A.G.B.T.), Department of MolecularNeuroscience (D.S.L., H.H.), UCL Institute of Neurology, and UCLEar Institute (D.-E.B.), University College London; LysholmDepartment of Neuroradiology (R.L., I.D.) and Department of Clin-ical and Experimental Epilepsy (S.H.E.), National Hospital forNeurology and Neurosurgery, London; and Department of Neurology(N.B.), Queen’s Medical Centre, Nottingham, United Kingdom.Author contributions: Yun Tae Hwang: clinical assessment. RahulLakshmanan: interpretation of MRI and preparation of the MRIfigure. Indran Davagnanam: interpretation of MRI and preparationof the MRI figure. Andrew D.B. Thompson: clinical assessment.David S. Lynch: genetic analysis. Henry Houlden: genetic analysis.Nin Bajaj: clinical assessment. Sofia H. Eriksson: assessment of poly-somnography. Doris-Eva Bamiou: neuro-otologic assessments and in-vestigations. Jason D. Warren: lead clinician. All authors wereinvolved in drafting and critically reviewing the manuscript.Acknowledgment: The authors are grateful to the patient for herinvolvement. They thank Marjo Van Der Knaap et al. at VU Uni-versity Medical Center, Amsterdam, for analysis of microsatellitemarkers.Study funding: This work was supported by the Alzheimer’s Society(AS-PG-16-007), the NIH Research University College LondonHospitals Biomedical Research Centre (CBRC 161), the LeonardWolfson Foundation, and the Wellcome Trust (091673/Z/10/Z).Disclosure: Y.T. Hwang has received travel funding from Guarantorsof Brain (United Kingdom). R. Lakshmanan, I. Davagnanam,A.G.B. Thompson, and D.S. Lynch report no disclosures. H. Houldenhas received research support from the Medical Research Council (MRC)UK, The BRT, TheMDAUSA, Muscular Dystrophy UK, Ataxia UK,Rosetrees Trust, The Wellcome Trust, and the National Institute forHealth Research (NIHR) UCL/UCLH BRC. N. Bajaj has receivedtravel funding from Bial Pharma Ltd.; is an employee of NHS UK; andFigure MRI and neuro-otologic findings in the present caseAxial T2-weighted MRI sections through the brainstem (A–C) and a coronal fluid-attenuated inversion recovery MRI section through the thalami (D) areshown. Red arrows (A) indicate involvement of the lateral lemnisci; dotted white arrows (B) indicate involvement of the superior olivary nuclei; solid whitearrows (C) indicate involvement of the dorsal, ventral, and inferior olivary nuclei. Pure tone audiometry plots (E) illustrate a “cookie-bite” profile of mildmidfrequency hearing loss in both right (red) and left (blue) ears (threshold [dB] on y axis, abnormal.20 dB; table e-1). Auditory brainstem evoked responses(F); 3 recordings displayed for left (above) and right (below) ears showing that peaks (length of vertical latency marker indicates amplitude 0.2 mV) for wave Vare consistently delayed beyond the normal range (gray oblongs) and normal latencies for waves I and III, indicating dysfunction of brainstem pathwaysbetween ventral cochlear nuclei and nucleus of the lateral lemniscus (table e-2). Note that these brainstem responses were evoked by a 6-kHz tone, whichhad a normal pure tone audiometric threshold for both ears (E).2 Neurology: Geneticshas received research support from the UK7T Network, the MedicalResearch Council (MRC) UK, the Michael J Fox Foundation, andParkinson’s UK. S.H. Eriksson has served on a data safety monitoringcommittee for Wellcome Trust; has received speaker honoraria fromEisai Pharma and UCB Pharma; has received travel funding fromUCB Pharma; and has received research support fromNIHRUniversityCollege London Hospitals Biomedical Research Centre. D.-E. Bamiouhas served on the editorial boards of Folia Phoniatrica et Logo-paedica and Hearing and Balance and Communication Disor-ders; has received research support from GNResound, EUEMBalance, and EU Evotion; and is an employee of UniversityCollege London. J.D. Warren has received research support fromWellcome Trust Senior Clinical Fellowship. Go to Neurology.org/ng for full disclosure forms. The Article Processing Chargewas funded by Wellcome Trust.This is an open access article distributed under the terms of theCreative Commons Attribution License 4.0 (CC BY), which permitsunrestricted use, distribution, and reproduction in any medium, pro-vided the original work is properly cited.Received March 3, 2017. Accepted in final form May 12, 2017.Correspondence to Prof. Warren: jason.warren@ucl.ac.uk1. Bugiani M, Kevelam SH, Bakels HS, et al. CathepsinA-related arteriopathy with strokes and leukoencephalop-athy (CARASAL). Neurology 2016;87:1777–1786.2. Lynch SD, de Paiva ARB, Zhang WJ, et al. Clinical andgenetic characterisation of leukoencephalopathies in adults.Brain (in press 2017).3. Cameron S, Dillon H, Newall P. Development and evalu-ation of the listening in spatialized noise test. Ear Hear2006;27:30–42.4. Haffner C, Vinters HV. CADASIL, CARASIL, CARASAL:the linguistic subtleties of cerebral small vessel disease. Neu-rology 2016;87:1752–1753.5. Ahmed RM, Murphy E, Davagnanam I, et al. A practicalapproach to diagnosing adult onset leukodystrophies.J Neurol Neurosurg Psychiatry 2014;85:770–781.6. Hardy CJ, Marshall CR, Golden HL, et al. Hearing anddementia. J Neurol 2016;263:2339–2354.7. Chabriat H, Mrissa R, Levy C, et al. Brain stem MRIsignal abnormalities in CADASIL. Stroke 1999;30:457–459.Neurology: Genetics 3DOI 10.1212/NXG.00000000000001652017;3; Neurol Genet Yun Tae Hwang, Rahul Lakshmanan, Indran Davagnanam, et al. leukoencephalopathyrelated arteriopathy with strokes and−Brainstem phenotype of cathepsin AThis information is current as of July 6, 2017reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2017 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet ServicesUpdated Information & http://ng.neurology.org/content/3/4/e165.full.htmlincluding high resolution figures, can be found at:Supplementary Material http://ng.neurology.org/content/suppl/2017/07/06/3.4.e165.DC1Supplementary material can be found at: References http://ng.neurology.org/content/3/4/e165.full.html##ref-list-1This article cites 6 articles, 2 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/mriMRI http://ng.neurology.org//cgi/collection/leukodystrophiesLeukodystrophies http://ng.neurology.org//cgi/collection/evoked_potentials-auditoryEvoked Potentials/Auditory http://ng.neurology.org//cgi/collection/all_neurotologyAll Neurotologyfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2017 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

Brainstem phenotype of cathepsin A-related arteriopathy with strokes and leukoencephalopathy

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Brainstem phenotype of cathepsin A-related arteriopathy with strokes and leukoencephalopathy

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